Generally speaking, the practice of medicine involves the diagnosis of a human disease from observed symptoms to develop a disease or injury hypothesis, the prescription and administration of a therapeutic treatment, e.g., a drug regimen and/or other therapy, the monitoring of the patient's adherence to self-administered treatment, particularly a drug regimen, the periodic assessment of the efficacy or lack of efficacy of the treatment, and the revision of the prescription and administration as necessary. The present invention is related to these practices in the particular context of assessing, monitoring and treating cardiac diseases.
The sympathetic division of the autonomic nervous system plays a major role in affecting cardiovascular function in both health and disease. Recently, it has been appreciated that what may begin as a short-term beneficial compensatory response by the sympathetic nervous system to impaired cardiac function, may lead to worsening of the disease state if increased sympathetic output continues unabated.
Sympatholytic cardiovascular agents, particularly, adrenergic stimulants (central) that decrease the sympathetic nerve output, as opposed to inhibiting only a subset of postsynaptic receptors, may be more effective than beta-blockers. A “centrally acting” sympatholytic cardiovascular agent is one that when administered by a conventional route, e.g. orally or by injection into the blood stream, is capable of crossing the blood-brain barrier and can produce effects on the central nervous system. Suitable centrally acting adrenergic stimulants include Aldoclor® (methyidopa and chlorothiazide sodium); Aldomet® (methyldopa); Aldomet® ester HCL (methyldopate HC1); Aldoril® (methyldopa and hydrochlorothiazide); Catapres® (clonidine HC1); Catapres®-TTS (clonidine); Clorpres® (clonidine hydrochloride and 25 chlorthalidone); Combipres® (clonidine hydrochloride and chlorthalidone); and Tenex® (guanfacine). Other centrally acting adrenergic stimulants include p-aminoclonidine guanabenz, lidamidine, tizanidine, moxonidine, xylazine, detomidine, medetomidine, and dexmedetomidine. It is also known that certain local anesthetics, e.g., lidocaine, bupivacaine, and ropivacaine that, when administered directly to a sympathetic nerve, have a local effect on the neurons that function in a sympatholytic manner. However, these local anesthetics that can act as a sympatholytic cardiovascular agent are not centrally acting, in that they cannot cross the blood-brain barrier.
Clonidine, also known as 2-[(2,6-dichlorophenyl)amino]-2-imidazoline is well known as a potent anti-hypertensive cardiovascular agent. Bolus intravenous injections of clonidine HCl have produced decreased sympathetic outflow, increased vagal tone and sensitivity of the baroreceptor reflex, with peak effects occurring at 5-20 minutes. Reductions were observed in heart rate, left ventricular filling pressure (preload), mean systemic arterial pressure (afterload), mean pulmonary artery pressure and right atrial pressure. See Giles, T. D. et al, “Acute Effects of Intravenous Clonidine HCl in Congestive Heart Failures”, Circulation, II, 62(4), October 1980. Oral administration of clonidine and its addition salts is asserted in U.S. Pat. No. 4,603,141 to be useful in the treatment of cardiac patients particularly to enhance exercise tolerance. The major side effects associated with oral or transdermal clonidine are sedation and dry mouth.
Clonidine and related compounds have other therapeutic uses than in the treatment of impaired cardiac function. Chronic pain is presently treated by intrathecal infusion of opioids (e.g., morphine, fentanyl, hydromorphone) through an intrathecal catheter from an implantable drug pump implanted in the patient's body or from an external drug pump worn externally by the patient. Recently, clonidine has also been approved for epidural infusion for the treatment of chronic pain (Duraclon®, Roxane Labs) and is typically administered in combination with opioids. Abnormally low blood pressure (hypotension) and bradycardia are reported as undesirable side effects accompanying intrathecal delivery of clonidine. Consequently, an effort is underway to develop a centrally acting alpha2-agonist causing less cardiovascular side effects, such as tizanidine.
The efficacy (or lack of efficacy) of the cardiovascular agent or agents delivered in a prescribed drug regimen must be carefully monitored and periodically assessed by the treating physician through use of patient interviews and a variety of tests. Patient data relevant to the state of health of a cardiac patient includes the patient's current ability to exercise and perform daily activities and the patient's self assessments that are periodically completed as set forth in commonly-assigned U.S. Pat. No. 6,280,409. The progression of cardiac disease and/or impairment and the efficacy of prescribed drug regiments can be assessed by periodically accurately measuring cardiac performance (e.g., ejection fraction) under a variety of metabolic conditions the patient is likely to encounter on a daily basis and typically employing external echocardiogram equipment in the clinical setting. However, the measurement procedure is time consuming to perform for even a resting patient and cannot be practically performed replicating a range of metabolic conditions. Typically, the echocardiography procedure is performed infrequently and months or years may lapse between successive tests, resulting in a poor understanding of the progress of the disease or whether or not intervening drug regimens have been efficacious.
A number of implantable cardiac monitors have been proposed and certain ones are clinically available. For example, a patient activity monitor is disclosed in the above-referenced '409 patent for implantation in a patient to record patient activity, e.g., walking, over a period of time. It may be concluded that the drug regimen is efficacious if the activity record exhibits increasing activity level over time or is either not efficacious or is not being adhered to by the patient if the activity record does not exhibit increasing activity level over time.
A monitor/stimulator is disclosed in U.S. Pat. No. 5,417,717 that monitors and assesses level of cardiac function then permits a physician to arbitrate the therapy mode, if therapy is indicated. The monitor/stimulator assesses impedance, EGM, and/or pressure measurements, and then calculates various cardiac parameters. The results of these calculations determine the mode of therapy to be chosen. Therapy may be administered by the monitor/stimulator itself or a control signal may be telemetry transmitted to various peripheral devices aimed at enhancing the heart's function. Alternatively, the monitor/stimulator may be programmed to monitor and either store or telemeter information without delivering therapy.
Implantable physiologic cardiac monitors for monitoring the mechanical and/or electrical heart function have been proposed and in some cases, implemented for deriving and storing EGM and mechanical performance data over a prolonged time.
It has been proposed, as described in commonly-assigned, co-pending U.S. patent application Ser. No. 10/002,338 filed Oct. 30, 2001, and Publication No. 2003/0100925 to employ various types of sensors including accelerometers, magnets, and sonomicrometers typically located in a blood vessel or heart chamber that respond to or move with mechanical heart function to derive a metric that changes in value over the heart cycle in proportion to the strength, velocity or range of motion of one or more of the heart chambers or valves. Such a mechanical function metric would complement the measurement of blood pressure and the EGM to more confidently determine the degree of change in the hemodynamic performance of the heart.
An implantable EGM monitor for recording the cardiac electrogram from electrodes remote from the heart as disclosed in commonly-assigned U.S. Pat. No. 5,331,966 and PCT publication WO 98/02209 is embodied in the Medtronic® REVEAL® Insertable Loop Recorder having spaced housing EGM electrodes. More elaborate implantable hemodynamic monitors (IHMs) for recording the EGM from electrodes placed in or about the heart and other physiologic sensor derived signals, e.g., one or more of blood pressure, blood gases, temperature, electrical impedance of the heart and/or chest, and patient activity have also been proposed. In particular, the Medtronic® CHRONICLE® Implantable Hemodynamic Monitor (IHM) system comprises a CHRONICLE® Model 9520 IHM of the type described in commonly-assigned U.S. Pat. No. 5,368,040 coupled with a Model 4328A pressure sensor lead that monitors the EGM of the heart and senses blood pressure within a heart chamber using a pressure sensing transducer of the type disclosed in commonly-assigned U.S. Pat. No. 5,564,434. The CHRONICLE® Model 9520 IHM measures absolute blood pressure, and the patient is also provided with an externally worn Medtronic® Model No. 2955HF atmospheric pressure reference monitor of the type described in commonly-assigned U.S. Pat. No. 5,810,735 to record contemporaneous atmospheric pressure values.
A variety of patient worn and implantable drug delivery systems have been developed that obviate the problems that arise from patient non-compliance with the prescribed drug regimen, that are convenient to use and enable more precise dosage titration, and that reduce side effects as a result of the dosage titration and because the drug can, in certain cases, be delivered to an optimal delivery site rather than being injected into the blood stream or ingested.
Implantable drug pumps having drug reservoirs that can be refilled through ports accessed transcutaneously and coupled with catheters extending from the reservoir to a delivery site have been developed or proposed to deliver a variety of drugs. The Medtronic® SynchroMed® Infusion System approved for certain clinical uses comprises an Implantable Infusion Pump (IIP) coupled to a catheter. The battery powered IIP can be advantageously programmed to frequently or continuously deliver drug boluses of drugs that have a short duration of activity directly to an efficacious site. The IIP is surgically implanted subcutaneously under the skin such that the refill port is directed outward. The IIP reservoir can be refilled as necessary. Adverse side effects are reduced and the mental and physical states of many patients are improved by the automatically administered drug therapy. It is not necessary to rely upon the patient to comply with the prescribed regimen.
The Medtronic® SynchroMed® Infusion System is approved for intrathecal drug delivery treatment of spasticity by intrathecal administration of baclofen and to reduce chronic pain by intraspinal administration of the opioids morphine and fentanyl. It has been proposed to deliver insulin into the central nervous system employing the Medtronic® SynchroMed® Infusion System in commonly-assigned, co-pending U.S. patent application Ser. No. 10/133,251 filed Apr. 26, 2002. One end of the drug infusion catheter is connected to the IIP, and the other end of the catheter is threaded into a cerebral spinal fluid (CSF) filled sub-arachnoid, intrathecal space in the patient's spinal cord. An IIP comprising an implantable pump and catheter is disclosed in commonly-assigned U.S. Pat. Nos. 5,643,207 and 5,782,798 for dispensing pancreatic polypeptide blockers and other drugs that decrease sensations of hunger and increase satiety into particular sites in the brain through a distal catheter segment that is implanted through the skull and extends to the specific sites.
Methods for administration of clonidine employing a Medtronic® SynchroMed® Infusion System to a human patient suffering from acute or chronic pain, most preferably neuropathic pain, are disclosed in commonly-assigned U.S. Pat. No. 5,801,188. An increasing dosage of clonidine is administered throughout a treatment regimen, wherein the amount of clonidine administered intraspinally is gradually increased over the treatment period to minimize adverse hemodynamic side effects. In preferred embodiments, the drug is administered intrathecally or epidurally, most preferably intrathecally, in a dosage of up to about 1200 mcg/day of clonidine over a treatment period of about 4 to 12 weeks. The amount of clonidine administered is increased periodically, preferably between once and about three times per day. Clonidine administration is increased by about 0.5 to about 5 mcg/hr during the administration period, resulting in a clinically effective dose of from about 4 to 50 mcg/hr.
It has also been proposed to implant multiple IMDs in the same patient, and to enable communication between the IMDs, whereby the multiple IMDs function cooperatively as disclosed, for example, in the above-referenced '409 patent and in commonly-assigned U.S. Pat. No. 4,987,897. The multiple IMDs include tissue stimulators, e.g., cardiac pacemakers, implantable cardioverter-defibrillators (ICDs), gastro-intestinal stimulators, deep brain stimulators, and spinal cord stimulators, implantable drug pumps, and implantable physiologic and activity sensors. It has been proposed in U.S. Pat. No. 5,330,505, for example, to combine the features of disparate IMDs, e.g. an implantable drug pump with a tissue or organ stimulator and with remote physiologic sensors, to provide multiple functions. In both cases, the IMD or IMDs communicate with external proximate medical devices, e.g., programmers and patient control units, and remote medical devices and systems employing a variety of data transmission techniques. In commonly-assigned U.S. Pat. No. 5,919,210, an IMD is disclosed that detects dysautonomic syncopes, e.g., vasovagal syncope, and endocardially infuses a drug in response thereto. A variety of sensors are placed in locations where the physiological activity to be detected is most prominent and more feasibly detected. Such sensors include, but are not limited to, those which can detect heart rate (R-R interval), atrio-ventricular interval (AVI), QT interval, QT/R-R ratio, heart rate variability indices such as HF, LF, LF/HF ratio, QRS or ventricular electrogram integral (area under depolarization signal), QRS duration, myocardial contractility index (accelerometer signal), subcutaneous blood flow mean value (SubQ BF), SubQ BF variability indices, motion, pH, temperature, position and chest wall impedance for monitoring respiration rate. The physiological activities used to determine the need for treatment include changes in heart rate, heart rate variability, QT interval, PR interval, pressure, blood flow, vagal nerve activity, temperature, pH, and AV conduction times, position, respiration rate and combinations thereof. The drug infusion catheter is placed according to the desired treatment regimen. For example, the drug infusion catheter may be placed within the coronary sinus, right atrium or right ventricle to provide rapid infusion with little dilution of pharmacological therapy.
A number of systems have been proposed to combine the delivery of an appropriate anti-arrhythmic drug therapy as an alternative or companion therapy with the delivery of an appropriate cardioversion/defibrillation shock as described, for example, in the above-referenced '897 patent and in U.S. Pat. Nos. 5,087,243 and 5,269,301. In these systems, an IIP is combined with an ICD, the system having a decision-making control algorithm to govern the diagnosis of the arrhythmia, prioritize the therapies to be delivered, and deliver the therapies. It is hoped that the delivered drug therapies can reduce the frequency of the need to deliver a cardioversion/defibrillation shock by either suppressing the tachyarrhythmia entirely or converting it to a lower rate or less chaotic tachyarrhythmia amenable to conversion by less aggressive high rate pacing therapies.
Combined neurological stimulation and/or drug delivery and cardiac therapy delivery devices are disclosed in further commonly-assigned co-pending U.S. Patent Application Publication Nos. US 2002/0165586, 2002/0143369, 2002/0107553, and 2003/0004549. Cardiac insult or anticipated cardiac insult is detected from monitored physiologic states, and electrical stimulation may be provided to peripheral nerves, intrinsic cardiac nerves, sympathetic ganglia, cranial nerves, and may generally be directed to the vertebral column, or within the chest wall of the patient. A drug delivery system optionally included in the system delivers biologically active agents based on the anticipation of the occurrence of the cardiac insult.
Despite the wide variety of IMDs and methods of treatment that have been proposed in the prior art, a need remains for an efficacious way of delivering drug therapies to patients who receive an acute cardiac insult, who suffer chronic cardiac pathologies, or who could benefit from a prophylactic cardiac therapy.